Methods have long been sought for extending the useful life of an implant that is inserted into the body. Not only is it important for an implant to last long enough to justify the cost, potential complications, and pain of implantation, but many situations exist in which there are strong medical reasons for maintaining the same implant within the body for an extended period of time. For example, when the implant is a sensor, having reliable, consistent, and continuous data from the same sensor can improve patient care.
Studies have shown that continuous measurement of biochemical analytes or drugs in the body significantly improves management and treatment of acute or chronic illnesses. For example, continuous monitoring may provide better control of diabetes, reducing the incidence of sequelae that lead to vision loss and impaired circulation. In trauma and congestive heart failure patients, the levels of lactate and glucose should be monitored simultaneously and continuously to facilitate detection of occult bleeding and changes in shock status. Real-time monitoring over the course of systemic administration of drugs or chemotherapeutic agents that have narrow ranges of effective concentration can provide the clinician with feedback upon which to make adjustments to dosing to assure proper concentrations are achieved and maintained.
Over a period of more than 20 years, many attempts have been made to develop an implanted sensor that provides frequent or continuous monitoring. For example, U.S. Pat. No. 4,703,756 to Gough et al., filed May 6, 1986, describes a sensor module for implantation in the body to monitor glucose and oxygen levels. When an apparatus having a sensor (or any other foreign body) is implanted, inflammatory and immune responses are initiated. Within minutes, protein (primarily fibrinogen) and platelets begin to adhere to the implant, followed over hours to days by recruitment of inflammatory and immune cells, which then surround the sensor. These initial tissue responses result in protein fouling of the sensor interface and potential degradation of the sensor chemistry by enzymes. Over the subsequent days and weeks, granulation tissue forms as the body attempts to repair the tissue damaged by the implantation procedure. Eventually, continued collagen production over the following weeks to months leads to formation of an avascular capsule surrounding the sensor and causes loss of analyte availability to the sensor. The avascular capsule is believed to be ultimately responsible for the majority of the drift of signal, loss of sensor sensitivity, and the need for frequent recalibration or even sensor replacement.
Various technologies have attempted to overcome this problem. For example, sensors have been developed that are placed intravascularly to avoid the problems of a capsule by allowing the tip of the sensor to be in continuous contact with the blood. However, placing a sensor directly into the vasculature puts the recipient at risk for thrombophlebosis, thromboembolism, and thrombophlebitis.
Sensors have also been developed that have physical features designed to address the problem of the foreign body response. For example, U.S. Pat. No. 6,212,416 to Ward et al. and U.S. Pat. No. 7,134,999 to Brauker et al. both offer architectural solutions. Ward et al. describe a movable outer membrane that can be renewed when it becomes fouled. Brauker et al. describe a sensor having a geometric design intended to minimize chronic inflammatory response at the sensing region of the sensor. However, these solutions do not permit the device to remain fully functional for long-term use, i.e., over a period of months or even years.
Attempts have been made to control the foreign body response by implanting therapeutic agents, e.g., tissue response modifiers, at the same time as the sensor. Such tissue response modifiers attempt to mask the presence of the implant within the body and reduce or eliminate the foreign body response. Vachon, in U.S. Pat. No. 6,212,416 describes a biosensor comprising an accessory material that includes a coating containing a hydrophilic material and/or a fiber modified to deliver a therapeutic agent. In U.S. Pat. No. 6,497,729, Moussey et al. describe a tissue/implant interface comprising a polymer layer that contains at least one tissue response modifier covalently attached to the polymer layer or entrapped within the polymer layer.
Such devices are successful in directing the foreign body response for a period of time that is limited by the amount of therapeutic agent that can be delivered along with the sensor. The mass of a drug or other compound necessary to consistently control the foreign body response over a period of 2-5 years is on the scale of hundreds to thousands of milligrams. This quantity is too large for a one-time administration or for incorporation into a drug reservoir feature of the sensor. Because the foreign body response increases when the size of the implant increases, delivering a sensor made larger by its accompanying therapeutic agent would be counterproductive. Furthermore, even if means were conceived to achieve a one-time delivery of a large quantity of a therapeutic agent, no known drugs or compounds for controlling a foreign body response are capable of remaining stable at body temperatures of 35° C. to 37° C. over a period of 2-5 years.
Therefore, it would be desirable to have an improved method for directing a localized biological response of a mammalian body to an implant and an implant system for long-term use that overcomes the aforementioned and other disadvantages. It would also be desirable to have a self-contained implant with electrical components that may be used to generate and/or measure one or more signals (e.g., analyte, electrical, optical, mechanical, magnetic and/or thermal signals).
Because the foreign body response increases when the size of the implant increases, having large electrical components in an implant can be counterproductive. A self-contained implant with, for example, a power source may be desirable to lessen the risk of infection from a percutaneous wire. Attempts to miniaturize apparatuses with sensors (e.g. analyte, electrical, optical, mechanical, magnetic and/or thermal sensors) may result in apparatuses for which a signal is not strong enough to be detected.
Implanted apparatuses that are larger than the cellular phagocytic size threshold become surrounded by immune cells and/or encapsulated and they lose their ability to accurately and rapidly sense blood-borne analytes in an unpredictable fashion. For implanted apparatuses that are below the phagocytic size threshold, they become engulfed by phagocytic cells and measure intracellular analyte levels instead of measuring analyte levels in the interstitial fluid as intended. Intracellular analyte levels are often irrelevant for systemic analyte monitoring, as is the case for continuous glucose monitors. The loss of contact between sensors and the interstitial fluid containing the analyte of interest, or the transport barriers imposed by the foreign body response are the primary reasons current sensing technologies typically fail after only a short time in the body (e.g., 2-7 days for commercially available sensors).
Thus, there remains a clear need for sensing technologies (e.g. analyte, electrical, optical, mechanical, magnetic and/or thermal sensing technologies) that are tissue integrating to provide long-term (e.g., weeks, months or years) and accurate readings by remaining in contact with interstitial fluid (not the internal cellular environment) and remaining in close proximity to the vasculature so that the interstitial fluid surrounding the sensor is in constant rapid equilibrium with nearby capillaries.